Changes to Individual Effectors, part 3
= Bone = Samuel Ahn Statement UCLA surgeon Samuel Ahn has theorized that ETS surgery would affect bone metabolism. At an educational conference in 2005, Ahn said: “Theoretically, if you cut the sympathetic nerves, you could interfere with bone metabolism . . .The reason I say that is because RSD Sympathetic Dystrophy is an over-activity of the sympathetic nerve. . . and we know that in RSD . . .we get a positive bone scan . . . because the bones are more active. So reverse this. If you take away the sympathetic drive to that bone area, you will decrease that metabolic activity in bone growth. And you could theoretically interfere with the bone metabolism and the bone strength. . .And that has been mentioned in the literature.” (edited for clarity, see Ahn 2005) Bone Remodeling Bones remodel themselves continually. They are constantly releasing calcium into the blood, while at the same time forming new bone from within. The cells which release calcium are called “osteo''clasts''”, and this process is called “resorption”. The cells which lay down new bone are called “osteo''blasts''”. In addition to laying down new bone, these osteoblasts also have the job of making new osteoclast cells. As with everything else, the control center is constantly trying maintain homeostasis of bone metabolism. “In the bone microenvironment, there is a dynamic balance between resorption and formation that maintains skeletal homeostasis”. (Kondo et al. 2003) center| Schematic of Bone Remodeling The control center (hypothalamus) receives signals from leptin in the blood. Acting on this information, it communicates to the osteoblast cells via the sympathetic nervous system. Ahn’s theorizing turns out to have tremendous merit. The notion that the sympathetic nervous system regulates bone metabolism has become accepted scientific fact. For example: “Bone remodeling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signaling via beta2-adrenergic receptors (b2-AR) present on osteoblasts controls bone formation downstream of leptin.” (Elefteriou et al. 2005, emphasis added) “Bone formation and osteoblast function are regulated by the sympathetic nervous system (SNS)” (Takeda et al. 2002) A team of Norwegian scientists put it this way: “'Sympathetic nerves are ''known to modulate bone resorption and bone remodeling'.” (Bletsa 2004, emphasis added) Thus it appears obvious that sympathectomy is going to alter bone metabolism in some way, the question is, how exactly? And, it would also be nice to know which bones, exactly, become denerved in thoracic sympathectomy. There appears to be a great lack of empirical data on patterns of SNS innervation to bone and bone marrow. More research is called for, and patients should be warned about potential changes in bone metabolism before consenting to ETS surgery. center| Does bone denervation follow the skin pattern, thus denerving the top 1/3 of the body’s bone mass? It seems certain that all bone in the arms and hands would have to be denerved. But perhaps the skull, jaw, ear bones, and/or teeth receive sympathetic innervation from somewhere above T2-T4. More data are sought. “The distinct effects of SP and catecholamines on the bone cells together with their in vivo influences manifested by experimental denervation studies suggest that the sensory and sympathetic nerves play important roles in bone metabolism.” (Imai et al. 2002) Yes, but what, exactly, is going to change about bone function in the denerved area? Sympathectomy and Bone Resorption “Higher numbers of osteoclasts and larger periapical lesions have been observed after sympathectomy in rats” (Bletsa 2004) “The sympathetic nervous system . . . has a significant effect on resorption by inhibiting preosteoclast differentiation and disturbing osteoclast activation. These data suggest that depletion of sympathetic mediators may disturb osteogenic cell-mediated osteoclast differentiation.” (Cherruau et al. 1999) “Sympathectomy increases bone resorption in gerbilline middle ear bone” (Sherman et al. 2001). Considering Sherman, a group of Norwegian orthodontists wanted to learn about resorption of teeth, so they performed sympathectomies on rats, (and gave them braces!) They found that “Sympathectomy causes increased root resorption after orthodontic tooth movement in rats”. (Haug et al. 2003) If sympathectomy changes bone resorption, how might it affect other aspects of bone metabolism? Sympathectomy and Cytokine Production “Cytokines” are chemical messengers of the immune system, for example interluken, and tumor necrosis factor (TNF). Tumor Necrosis Factor helps kill tumors. Could sympathectomy affect the production of cytokines? The Norwegian orthodontists wondered the same thing, so the following year they did more rat sympathectomies to look for changes in the production of cytokines Interlukin 1 alpha and TNF alpha in their teeth. “This study suggests that sympathetic nerves have an inhibitory effect on IL-1alpha . . .and a stimulatory effect on TNF-alpha in the intact rat pulp.” (Bletsa 2004) Leptin Leptin is a hormone released by fat cells into the blood stream. It acts as a chemical messenger by interacting with receptors in the hypothalamus. Enough leptin in the blood tells the control center “we’re full, stop eating”. But leptin also regulates bone metabolism. Leptin regulates bone metabolism via the SNS, this much is clear. It has been suggested that perhaps there is a negative feedback loop, wherein the reverse is also true. Perhaps the SNS also is able to regulate leptin production in some way. Some doctors at a VA hospital in Iowa thought so, and reported in their 2003 paper “There is evidence that sympathoadrenal stimulation inhibits leptin mRNA expression and secretion from white adipose tissue through beta adrenergic mechanisms.” (Mark et al. 2003) We’ve already learned that sympathectomy will increase fat cell count and mass, which would lead to an increase in leptin. Now we see evidence that the normal SNS inhibits the production of leptin, so sympathectomy would be predicted increase the production of leptin even disregarding the higher fat cell count and mass. What is the effect of leptin on bone metabolism? “Leptin is a powerful inhibitor of bone formation in vivo.” (Elefteiou et al. 2004). This would tend to reinforce the bone resorption increase already noted. Calcium lost form bone must go somewhere, and that somewhere is into the blood. Considering this extra calcium, and considering the lowered blood catecholamines, we can offer the next prediction. Sympathectomy and Monckeberg’s Sclerosis Back in 1983 a pair of surgeons were experimenting using lumbar sympathectomy to treat the circulation problems associated with diabetes. After 6-8 year follow up, they discovered that sympathectomy was causing a severe calcification of the arteries, a condition known as “Monckeberg’s Sclerosis”. It became especially clear to them because they had a number of patients who had only been sympathectomized on one side, and the incidence of the calcification was far higher on that side. “After unilateral sympathectomy the incidence of calcified arteries on the side of operation was significantly higher than that on the contralateral side (88% versus 18%, p less than 0.01). In conclusion, '''sympathetic denervation is one of the causes of Monckeberg's sclerosis' regardless of diabetes mellitus.” (Goebel et al. 1983, emphasis added) Bone Marrow Stem Cells 2006 saw the publication of an article entitled “Signals from the Sympathetic Nervous System Regulate Hematopoietic Stem Cell Egress from Bone Marrow”. Hematopoietic stem cells and progenitor cells, or HSPCs, are the precursors for red blood cells. We learn from the paper that “Hematopoietic stem and progenitor cells (HSPCs) reside in specific niches that control survival, proliferation, self-renewal, or differentiation in the bone marrow (BM). The sympathetic nervous system regulates the attraction of stem cells to their niche.” (Katayama, et. al. 2006, emphasis added). = Thyroid Gland = Sympathetic Innervation of Thyroid The thyroid is located in the neck, and is a two sided gland responsible for releasing various hormones into the blood. It is predominantly controlled by Thyroid Stimulating Hormone (TSH) released by the pituitary, which in turn is regulated by the hypothalamus. This much has been known for some time. Additionally, the thyroid has sympathetic innervation, the role of which is less clear. The chemical iodide is absorbed by the thyroid, and converted into iodine, which is essential for proper thyroid function. center| Schematic of Sympathetic Innervation of the Thyroid Thyroid PET Scan After ETS center| 'PET Scan of Neck After T2-T4 ETS ' '' Flourodopamine PET scan of the human neck after T2-T4 sympathectomy. The butterfly-shaped outline indicates the approximate location of the thyroid. According to NIH’s David Goldstein, who took the scan, the lack of yellow-orange-red color within the outline indicates total sympathetic denervation of the thyroid. A normal scan is sought for comparison.'' Thus we find evidence that the thyroid gland is innervated entirely between T2 and T4. More data are sought. Rat Thyroid Study What is the role of the SNS on thyroid function? Scientists at Northwestern University were puzzled, so they denerved rat thyroids on one side only. They injected a radioactive form of iodide known as 125I, so that the results on iodide uptake could be visualized. “Unilateral superior cervical ganglion decentralization led to a reduction in thyroid weight, in 125I uptake by thyroid tissue, and in TSH-induced stimulation of 125I uptake in decentralized hemithyroids. These results suggest that sympathetic activity in thyroid contributes to gland enlargement and may modulate tissue responsiveness to TSH.” (Young et al., 2005). Iodine deficiency is associated with hypothyroidism (low thyroid function), thus: Some of the symptoms of hypothyroidism are similar to some of the common anecdotal complaints of ETS patients. From the Mayo Clinic website, we gather: Symptoms of Hypothyroidism * Increased sensitivity to cold * Constipation * Pale, dry skin * A puffy face * Hoarse voice * An elevated blood cholesterol level * Unexplained weight gain * Muscle aches, tenderness and stiffness * Pain, stiffness or swelling in your joints * Muscle weakness * Heavier than normal menstrual periods * Depression = Eyes and Eyelids = Innervation of the Eyes The eyes and eyelids have both sympathetic and parasympathetic innervation. Two sets of muscles surround the pupils – radial and sphincter. Radial muscles, which have mostly sympathetic innervation, dilate the pupil; while sphincter muscles, which have mostly parasympathetic innervation, serve to constrict. The pupils will respond to changes in lighting by attempting to allow a more-or-less constant amount of light onto the retina, constricting if the light is too bright, dilating when it gets darker. Pupils also respond to various emotions; dilating with passionate love, for example. Pupil responses to emotion operate in a classic reciprocal fashion, as sympathetic tone goes up, parasympathetic goes down, and the pupil dilates. Curiously, pupil responses to light are almost entirely mediated by the PSNS. An increase in parasympathetic tone constricts the pupil, withdrawal dilates it. Eyelids operate both voluntarily and autonomically. An increase in sympaththetic tone will serve to open the eyelid extra wide, for extra visibility and alertness. This is also a body language cue of sexual attraction. Horner’s Syndrome The eyes and eyelids receive post-ganglionic innervation from about C1-T1, just above the level normally targeted in ETS surgery. If T1 is accidentally damaged, sympathetic innervation to the eyes and eyelids may be interrupted, resulting in “Horner’s Syndrome”. Horner’s Syndrome is characterized by an overly constricted pupil, and a drooping eyelid. The eyeball may sink lower in the eye socket, and suffer soreness, redness and a lack of moisture.